|
1
|
Hanusrichterova J, Baranovicova E, Barosova R, Kolomaznik M, Mikolka P, Kosutova P, Mokra D, Mokry J, Calkovska A. Metabolic profiling in experimental guinea pig models of bacterial and allergic inflammation. Metabolomics 2025; 21:43. [PMID: 40123009 PMCID: PMC11930882 DOI: 10.1007/s11306-025-02239-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 02/11/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Based on distinct triggers, bacterial and allergen-induced inflammatory reactions have different pathophysiology. Metabolomic analysis is high-throughput technique that can provide potential biomarkers to distinguish between these responses. OBJECTIVES In order to find out the metabolic profiles of two types of inflammation, metabolites were analysed in blood plasma and bronchoalveolar lavage fluid (BALF) of guinea pigs subjected to bacterial lipopolysaccharide (LPS) or allergen ovalbumin (OVA). METHODS Hydrogen-1 nuclear magnetic resonance (1H NMR) spectroscopy for metabolite analysis was performed in samples of blood plasma and BALF of guinea pigs. RESULTS Random forest algorithm built on combination of levels of circulating and BALF metabolites resulted in almost ideal discrimination between acute allergic and bacterial inflammation. The differences between inflammation triggered by LPS and OVA were manifested in shift in energy metabolism, metabolism of branched-chain amino acids (BCAAs)/branched-chain keto acids (BCKAs) with alterations in alanine and glutamine, which are linked with both, ammonia homeostasis as well as gluconeogenesis. CONCLUSION Distinct molecule nutrients are to be utilized during acute bacterial and allergic inflammatory response.
Collapse
Affiliation(s)
- J Hanusrichterova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 11161/4D, 03601, Martin, Slovakia.
| | - E Baranovicova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 11161/4D, 03601, Martin, Slovakia
| | - R Barosova
- Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 11161/4C, 03601, Martin, Slovakia
| | - M Kolomaznik
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 11161/4D, 03601, Martin, Slovakia
| | - P Mikolka
- Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 11161/4C, 03601, Martin, Slovakia
| | - P Kosutova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 11161/4D, 03601, Martin, Slovakia
| | - D Mokra
- Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 11161/4C, 03601, Martin, Slovakia
| | - J Mokry
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 11161/4C, 03601, Martin, Slovakia
| | - A Calkovska
- Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 11161/4C, 03601, Martin, Slovakia
| |
Collapse
|
|
2
|
Lin L, Guo Z, Ren Z, Feng Y, Fang P, Wang T, Chen M. Bibliometric insights into astrocytic roles in depression and treatment. Front Cell Neurosci 2025; 18:1521398. [PMID: 39882216 PMCID: PMC11775634 DOI: 10.3389/fncel.2024.1521398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Objective Depression is a mental disorder that significantly impairs both physical and mental health. Recent studies have shown that reactive astrogliosis have gained significant attention for their involvement in the pathophysiology of depression. However, there is no bibliometric analysis in this research field. This study aims to provide a comprehensive overview of the knowledge structure and research hotspots regarding the role of astrocytes in the mechanisms and treatment of depression through bibliometric analysis. The scope of the literature review encompasses both basic and clinical research. Methods Publications related to astrocytes in depression and treatment from 2014 to 2023 were searched in the Web of Science Core Collection (WoSCC) database. VOSviewer, CiteSpace, and the R package "bibliometrix" were used to conduct this bibliometric analysis. Results From 2014 to 2023, a total of 1,502 documents from 78 countries on astrocytes in depression and treatment were analyzed from 169 journals, with the most co-cited journals being the Journal of Neuroscience and PNAS. China Medical University was the most productive institution. The analysis identified key authors like Verkhratsky Alexei and Baoman Li, and major co-cited references by Rajkowska and Liddelow. Keywords such as "synaptic plasticity," "astrocytes," and "neuroinflammation" revealed research trends focusing on molecular mechanisms, gut microbiota, and inflammation. Conclusion This is the first bibliometric study to comprehensively summarize the research trends and advancements regarding astrocytes in depression and its treatment. Through this bibliometric analysis, we aim to enhance the understanding of the significance of astrocytes in depression research and provide new perspectives and insights for future investigations. We hope that this study will facilitate a broader integration of basic and clinical research, offering novel approaches for the treatment of depression.
Collapse
Affiliation(s)
- Linsun Lin
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macao SAR, China
- Huizhou Health Sciences Polytechnic, Huizhou, China
| | - Ziyi Guo
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhuoyu Ren
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanchen Feng
- The First Clinical Medical School, Henan University of Chinese Medicine, Zhengzhou, China
| | - Peigang Fang
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macao SAR, China
| | - Tao Wang
- Encephalopathy Center, The Second Affiliation Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Min Chen
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macao SAR, China
- Guangdong Medical University, Zhanjiang, China
| |
Collapse
|
|
3
|
Dóra F, Hajdu T, Renner É, Paál K, Alpár A, Palkovits M, Chinopoulos C, Dobolyi A. Reverse phase protein array-based investigation of mitochondrial genes reveals alteration of glutaminolysis in the parahippocampal cortex of people who died by suicide. Transl Psychiatry 2024; 14:479. [PMID: 39604371 PMCID: PMC11603240 DOI: 10.1038/s41398-024-03137-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/20/2024] [Accepted: 09/26/2024] [Indexed: 11/29/2024] Open
Abstract
A moderating hub between resting state networks (RSNs) and the medial temporal lobe (MTL) is the parahippocampal cortex (PHC). Abnormal activity has been reported in depressed patients and suicide attempters in this region. Alterations in neuronal mitochondrial function may contribute to depression and suicidal behavior. However, little is known about the underlying molecular level changes in relevant structures. Specifically, expressional changes related to suicide have not been reported in the PHC. In this study, we compared the protein expression levels of genes encoding tricarboxylic acid (TCA) cycle enzymes in the PHC of adult individuals who died by suicide by reverse phase protein array (RPPA), which was corroborated by qRT-PCR at the mRNA level. Postmortem human brain samples were collected from 12 control and 10 suicidal individuals. The entorhinal cortex, which is topographically anterior to the PHC in the parahippocampal gyrus, and some other cortical brain regions were utilized for comparison. The results of the RPPA analysis revealed that the protein levels of DLD, OGDH, SDHB, SUCLA2, and SUCLG2 subunits were significantly elevated in the PHC but not in other cortical brain regions. In accordance with these findings, the mRNA levels of the respective subunits were also increased in the PHC. The subunits with altered levels are implicated in enzyme complexes involved in the oxidative decarboxylation branch of glutamine catabolism. These data suggest a potential role of glutaminolysis in the pathophysiology of suicidal behavior in the PHC.
Collapse
Affiliation(s)
- Fanni Dóra
- Human Brain Tissue Bank, Semmelweis University, Budapest, 1094, Hungary
- Laboratory of Neuromorphology, Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, 1094, Hungary
| | - Tamara Hajdu
- Laboratory of Neuromorphology, Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, 1094, Hungary
- Department of Physiology and Neurobiology, Eötvös Loránd University, Budapest, 1117, Hungary
| | - Éva Renner
- Human Brain Tissue Bank, Semmelweis University, Budapest, 1094, Hungary
| | - Krisztina Paál
- Department of Biochemistry and Molecular Biology, Semmelweis University, Budapest, 1094, Hungary
| | - Alán Alpár
- Human Brain Tissue Bank, Semmelweis University, Budapest, 1094, Hungary
- Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, 1094, Hungary
| | - Miklós Palkovits
- Human Brain Tissue Bank, Semmelweis University, Budapest, 1094, Hungary
| | - Christos Chinopoulos
- Department of Biochemistry and Molecular Biology, Semmelweis University, Budapest, 1094, Hungary.
| | - Arpád Dobolyi
- Laboratory of Neuromorphology, Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, 1094, Hungary.
- Department of Physiology and Neurobiology, Eötvös Loránd University, Budapest, 1117, Hungary.
| |
Collapse
|
|
4
|
Anthony DC, Probert F, Gorlova A, Hebert J, Radford-Smith D, Nefedova Z, Umriukhin A, Nedorubov A, Cespuglio R, Shulgin B, Lyundup A, Lesch KP, Strekalova T. Impact of Serotonin Transporter Absence on Brain Insulin Receptor Expression, Plasma Metabolome Changes, and ADHD-like Behavior in Mice fed a Western Diet. Biomolecules 2024; 14:884. [PMID: 39199273 PMCID: PMC11351952 DOI: 10.3390/biom14080884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/02/2024] [Accepted: 07/15/2024] [Indexed: 09/01/2024] Open
Abstract
The impaired function of the serotonin transporter (SERT) in humans has been linked to a higher risk of obesity and type 2 diabetes, especially as people age. Consuming a "Western diet" (WD), which is high in saturated fats, cholesterol, and sugars, can induce metabolic syndrome. Previous research indicated that mice carrying a targeted inactivation of the Sert gene (knockout, KO) and fed a WD display significant metabolic disturbances and behaviors reminiscent of ADHD. These abnormalities might be mediated via a dysfunction in insulin receptor (IR) signaling, which is also associated with adult ADHD. However, the impact of Sert deficiency on IR signaling and systemic metabolic changes has not been thoroughly explored. In this study, we conducted a detailed analysis of locomotor behavior in wild-type (WT) and KO mice fed a WD or control diet. We investigated changes in the blood metabolome and examined, via PCR, the expression of insulin receptor A and B isoforms and key regulators of their function in the brain. Twelve-month-old KO mice and their WT littermates were fed a WD for three weeks. Nuclear magnetic resonance spectroscopy analysis of plasma samples showed that KO mice on a WD had higher levels of lipids and lipoproteins and lower levels of glucose, lactate, alanine, valine, and isoleucine compared to other groups. SERT-KO mice on the control diet exhibited increased brain levels of both IR A and B isoforms, accompanied by a modest increase in the negative regulator ENPP. The KO mice also displayed anxiety-like behavior and reduced exploratory activity in an open field test. However, when the KO animals were fed a WD, the aberrant expression levels of IR isoforms in the KO mice and locomotor behavior were ameliorated indicating a complex interaction between genetic and dietary factors that might contribute to ADHD-like symptoms. Overall, our findings suggest that the lack of Sert leads to a unique metabolic phenotype in aged mice, characterized by dysregulated IR-related pathways. These changes are exacerbated by WD in the blood metabolome and are associated with behavioral abnormalities.
Collapse
Affiliation(s)
- Daniel C. Anthony
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK; (D.C.A.); (F.P.); (J.H.); (D.R.-S.)
| | - Fay Probert
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK; (D.C.A.); (F.P.); (J.H.); (D.R.-S.)
- Department of Chemistry, Oxford University, Oxford OX1 2JD, UK
| | - Anna Gorlova
- Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.G.); (R.C.); (A.L.)
| | - Jenna Hebert
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK; (D.C.A.); (F.P.); (J.H.); (D.R.-S.)
| | - Daniel Radford-Smith
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK; (D.C.A.); (F.P.); (J.H.); (D.R.-S.)
| | - Zlata Nefedova
- Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (Z.N.); (A.U.); (A.N.)
| | - Aleksei Umriukhin
- Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (Z.N.); (A.U.); (A.N.)
| | - Andrey Nedorubov
- Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (Z.N.); (A.U.); (A.N.)
| | - Raymond Cespuglio
- Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.G.); (R.C.); (A.L.)
| | - Boris Shulgin
- Laboratory of Engineering Profile Physical and Chemical Methods of Analysis, Korkyt Ata Kyzylorda University, Kyzylorda 120014, Kazakhstan;
| | - Aleksey Lyundup
- Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.G.); (R.C.); (A.L.)
- Endocrinology Research Centre, Dmitry Ulyanov Str. 19, 117036 Moscow, Russia
| | - Klaus Peter Lesch
- Division of Molecular Psychiatry, Center of Mental Health, University Hospital Würzburg, 97080 Würzburg, Germany;
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Tatyana Strekalova
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK; (D.C.A.); (F.P.); (J.H.); (D.R.-S.)
| |
Collapse
|
|
5
|
Strekalova T, Radford-Smith D, Dunstan IK, Gorlova A, Svirin E, Sheveleva E, Burova A, Morozov S, Lyundup A, Berger G, Anthony DC, Walitza S. Omega-3 alleviates behavioral and molecular changes in a mouse model of stress-induced juvenile depression. Neurobiol Stress 2024; 31:100646. [PMID: 38912378 PMCID: PMC11190747 DOI: 10.1016/j.ynstr.2024.100646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 04/29/2024] [Accepted: 05/19/2024] [Indexed: 06/25/2024] Open
Abstract
Introduction Depression is increasingly diagnosed in adolescence, necessitating specific prevention and treatment methods. However, there is a lack of animal models mimicking juvenile depression. This study explores a novel model using ultrasound (US) stress in juvenile mice. Methods We employed the US stress model in one-month-old C57/BL6 mice, exposing them to alternating ultrasound frequencies (20-25 kHz and 25-45 kHz) for three weeks. These frequencies correspond to negative and neutral emotional states in rodents and can induce a depressive-like syndrome. Concurrently, mice received either an omega-3 food supplement (FS) containing eicosapentaenoic acid (EPA; 0.55 mg/kg/day) and docosahexaenoic acid (DHA; 0.55 mg/kg/day) or a vehicle. Post-stress, we evaluated anxiety- and depressive-like behaviors, blood corticosterone levels, brain expression of pro-inflammatory cytokines, and conducted metabolome analysis of brain, liver and blood plasma. Results US-exposed mice treated with vehicle exhibited decreased sucrose preference, a sign of anhedonia, a key feature of depression, increased anxiety-like behavior, elevated corticosterone levels, and enhanced TNF and IL-1β gene expression in the brain. In contrast, US-FS mice did not display these changes. Omega-3 supplementation also reduced anxiety-like behavior in non-stressed mice. Metabolomic analysis revealed US-induced changes in brain energy metabolism, with FS increasing brain sphingomyelin. Liver metabolism was affected by both US and FS, while plasma metabolome changes were exclusive to FS. Brain glucose levels correlated positively with activity in anxiety tests. Conclusion Chronic omega-3 intake counteracted depressive- and anxiety-like behaviors in a US model of juvenile depression in mice. These effects likely stem from the anti-inflammatory properties of the supplement, suggesting potential therapeutic applications in juvenile depression.
Collapse
Affiliation(s)
- Tatyana Strekalova
- Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands
- Department of Pharmacology, Oxford University, Oxford, UK
| | | | | | - Anna Gorlova
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
- RUDN University, 6 Miklukho-Maklaya Str, Moscow, Russia
| | - Evgeniy Svirin
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Elisaveta Sheveleva
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
- Department of Normal Physiology, Sechenov Moscow State Medical University, Moscow, Russia
| | - Alisa Burova
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Sergey Morozov
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Aleksey Lyundup
- RUDN University, 6 Miklukho-Maklaya Str, Moscow, Russia
- Endocrinology Research Centre, Dmitry Ulyanov str. 19, Moscow, 117036, Russia
| | - Gregor Berger
- Department of Child and Adolescent Psychiatry and Psychotherapy, University of Zuerich, Zuerich, Switzerland
| | | | - Susanne Walitza
- Department of Child and Adolescent Psychiatry and Psychotherapy, University of Zuerich, Zuerich, Switzerland
| |
Collapse
|
|
6
|
Gu ZW, Zhang CP, Chen LP, Huang X. Clinical effects of nonconvulsive electrotherapy combined with mindfulness-based stress reduction and changes of serum inflammatory factors in depression. World J Psychiatry 2024; 14:653-660. [PMID: 38808093 PMCID: PMC11129146 DOI: 10.5498/wjp.v14.i5.653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/13/2024] [Accepted: 04/12/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Depression is a common and serious psychological condition, which seriously affects individual well-being and functional ability. Traditional treatment methods include drug therapy and psychological counseling; however, these methods have different degrees of side effects and limitations. In recent years, nonconvulsive electrotherapy (NET) has attracted increasing attention as a noninvasive treatment method. However, the clinical efficacy and potential mechanism of NET on depression are still unclear. We hypothesized that NET has a positive clinical effect in the treatment of depression, and may have a regulatory effect on serum inflammatory factors during treatment. AIM To assess the effects of NET on depression and analyze changes in serum inflammatory factors. METHODS This retrospective study enrolled 140 patients undergoing treatment for depression between May 2017 and June 2022, the observation group that received a combination of mindfulness-based stress reduction (MBSR) and NET treatment (n = 70) and the control group that only received MBSR therapy (n = 70). The clinical effectiveness of the treatment was evaluated by assessing various factors, including the Hamilton Depression Scale (HAMD)-17, self-rating idea of suicide scale (SSIOS), Pittsburgh Sleep Quality Index (PSQI), and levels of serum inflammatory factors before and after 8 wk of treatment. The quality of life scores between the two groups were compared. Comparisons were made using t and χ2 tests. RESULTS After 8 wk of treatment, the observation group exhibited a 91.43% overall effectiveness rate which was higher than that of the control group which was 74.29% (64 vs 52, χ2 = 7.241; P < 0.05). The HAMD, SSIOS, and PSQI scores showed a significant decrease in both groups. Moreover, the observation group had lower scores than the control group (10.37 ± 2.04 vs 14.02 ± 2.16, t = 10.280; 1.67 ±0.28 vs 0.87 ± 0.12, t = 21.970; 5.29 ± 1.33 vs 7.94 ± 1.35, t = 11.700; P both < 0.001). Additionally, there was a notable decrease in the IL-2, IL-1β, and IL-6 in both groups after treatment. Furthermore, the observation group exhibited superior serum inflammatory factors compared to the control group (70.12 ± 10.32 vs 102.24 ± 20.21, t = 11.840; 19.35 ± 2.46 vs 22.27 ± 2.13, t = 7.508; 32.25 ± 4.6 vs 39.42 ± 4.23, t = 9.565; P both < 0.001). Moreover, the observation group exhibited significantly improved quality of life scores compared to the control group (Social function: 19.25 ± 2.76 vs 16.23 ± 2.34; Emotions: 18.54 ± 2.83 vs 12.28 ± 2.16; Environment: 18.49 ± 2.48 vs 16.56 ± 3.44; Physical health: 19.53 ± 2.39 vs 16.62 ± 3.46; P both < 0.001) after treatment. CONCLUSION MBSR combined with NET effectively alleviates depression, lowers inflammation (IL-2, IL-1β, and IL-6), reduces suicidal thoughts, enhances sleep, and improves the quality of life of individuals with depression.
Collapse
Affiliation(s)
- Zhi-Wen Gu
- Department of Psychiatry, Guangzhou First People's Hospital, South China University of Technology, Guangzhou 510180, Guangdong Province, China
| | - Chun-Ping Zhang
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou HuiAi Hospital), Guangzhou 510370, Guangdong Province, China
| | - Li-Ping Chen
- Department of Psychiatry, Guangzhou First People's Hospital, South China University of Technology, Guangzhou 510180, Guangdong Province, China
| | - Xiong Huang
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou HuiAi Hospital), Guangzhou 510370, Guangdong Province, China
| |
Collapse
|
|
7
|
Kinra M, Ranadive N, Nampoothiri M, Arora D, Mudgal J. Involvement of NLRP3 inflammasome pathway in the protective mechanisms of ferulic acid and p-coumaric acid in LPS-induced sickness behavior and neuroinflammation in mice. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1829-1839. [PMID: 37755515 PMCID: PMC10858824 DOI: 10.1007/s00210-023-02743-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 09/21/2023] [Indexed: 09/28/2023]
Abstract
Ferulic acid (FA) and p-coumaric acid (PCA) are abundantly present in commonly consumed food and beverages. Being polyphenolic compounds, they have been explored for their antioxidant and anti-inflammatory properties. Based on our previous study, we selected these two compounds to further investigate their potential in lipopolysaccharide (LPS)-induced sickness behavior and the ensuing neuroinflammation by specifically focusing on the NLRP3 inflammasome pathway. Male Swiss albino mice were divided into nine groups (n = 6) consisting of Normal Control, LPS, fluoxetine (FLX), FA40, FA160, FA640, PCA40, PCA160, and PCA640 respectively. Each group received respective FA or PCA treatment except Normal Control and LPS, which received the vehicle, carboxymethylcellulose 0.25% w/v. All groups were challenged with LPS 1.5 mg/kg, intraperitoneally except the Normal Control group, which received saline. Behavioral assessments were performed between 1-2 h, and the whole brains were collected at 3 h post-LPS administration. LPS-induced sickness behavior was characterized by significantly reduced spontaneous activity and high immobility time. The expression of NLRP3, ASC, caspase-1 and IL-1β was significantly increased, along with the levels of brain IL-1β suggesting the assembly and activation of NLRP3 inflammasome pathway. Furthermore, the major cytokines involved in sickness behavior, IL-6 and TNF-α were also significantly elevated with the accompanied lipid peroxidation. The results of this study emphasize that within the employed dose ranges of both FA and PCA, both the compounds were effective at blocking the activation of the NLRP3 inflammasome pathway and thereby reducing the release of IL-1β and the sickness behavior symptoms. There was a prominent effect on cytokine levels and lipid peroxidation as well.
Collapse
Affiliation(s)
- Manas Kinra
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Niraja Ranadive
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Devinder Arora
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast Campus, Gold Coast, QLD, 4222, Australia.
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
| |
Collapse
|
|
8
|
Dunstan IK, McLeod R, Radford-Smith DE, Xiong W, Pate T, Probert F, Anthony DC. Unique pathways downstream of TLR-4 and TLR-7 activation: sex-dependent behavioural, cytokine, and metabolic consequences. Front Cell Neurosci 2024; 18:1345441. [PMID: 38414751 PMCID: PMC10896997 DOI: 10.3389/fncel.2024.1345441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 02/01/2024] [Indexed: 02/29/2024] Open
Abstract
Introduction Post-infection syndromes are characterised by fatigue, muscle pain, anhedonia, and cognitive impairment; mechanistic studies exploring these syndromes have focussed on pathways downstream of Toll-like receptor (TLR) 4 activation. Here, we investigated the mechanistic interplay between behaviour, metabolism, and inflammation downstream of TLR-7 activation compared to TLR-4 activation in male and female CD1 mice. Methods Animals received either a TLR-4 (LPS; 0.83 mg/kg) or TLR-7 (R848, 5 mg/kg) agonist, or saline, and behaviour was analysed in an Open Field (OF) at 24 h (n = 20/group). Plasma, liver, and prefrontal cortex (PFC) were collected for gene expression analysis at 24 h and 1H-NMR metabolomics. Results TLR-4 and TLR-7 activation decreased distance travelled and rearing in the OF, but activation of each receptor induced distinct cytokine responses and metabolome profiles. LPS increased IL-1β expression and CXCL1 in the PFC, but TLR7 activation did not and strongly induced PFC CXCL10 expression. Thus, TLR7 induced sickness behaviour is independent of IL-1β expression. In both cases, the behavioural response to TLR activation was sexually dimorphic: females were more resilient. However, dissociation was observed between the resilient female mice behaviour and the levels of gene cytokine expression, which was, in general, higher in the female mice. However, the metabolic shifts induced by immune activation were better correlated with the sex-dependent behavioural dimorphisms; increased levels of antioxidant potential in the female brain are intrinsic male/female metabolome differences. A common feature of both TLR4 and TLR7 activation was an increase in N-acetyl aspartate (NAA) in the PFC, which is likely be an allostatic response to the challenges as sickness behaviour is inversely correlated with NAA levels. Discussion The results highlight how the cytokine profile induced by one PAMP cannot be extrapolated to another, but they do reveal how the manipulation of the conserved metabolome response might afford a more generic approach to the treatment of post-infection syndromes.
Collapse
Affiliation(s)
- Isobel K. Dunstan
- Medical Sciences Division, Department of Pharmacology, University of Oxford, Oxford, United Kingdom
- Department of Chemistry, Mathematical, Physical and Life Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Ross McLeod
- Medical Sciences Division, Department of Pharmacology, University of Oxford, Oxford, United Kingdom
- Department of Chemistry, Mathematical, Physical and Life Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Daniel E. Radford-Smith
- Medical Sciences Division, Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Wenzheng Xiong
- Medical Sciences Division, Department of Pharmacology, University of Oxford, Oxford, United Kingdom
- Department of Chemistry, Mathematical, Physical and Life Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Trinity Pate
- Medical Sciences Division, Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Fay Probert
- Medical Sciences Division, Department of Pharmacology, University of Oxford, Oxford, United Kingdom
- Department of Chemistry, Mathematical, Physical and Life Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Daniel C. Anthony
- Medical Sciences Division, Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
9
|
Siddiqui F, Gallagher D, Shuster-Hyman H, Lopez L, Gauthier-Fisher A, Librach CL. First trimester human umbilical cord perivascular cells (HUCPVC) modulate the kynurenine pathway and glutamate neurotransmission in an LPS-induced mouse model of neuroinflammation. J Inflamm (Lond) 2023; 20:15. [PMID: 37127610 PMCID: PMC10152638 DOI: 10.1186/s12950-023-00340-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 04/17/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND The Kynurenine Pathway (KP) of tryptophan degradation and glutamate toxicity is implicated in several neurological disorders, including depression. The therapeutic potential of mesenchymal stromal cells (MSC), owing to their well documented phagocytosis-driven mechanism of immunomodulation and neuroprotection, has been tested in many neurological disorders. However, their potential to influence KP and the glutamatergic system has not yet been investigated. Hence, this study sought to investigate the effect of HUCPVC, a rich and potent source of MSC, on Lipopolysaccharide (LPS)-activated KP metabolites, KP enzymes, and key components of glutamate neurotransmission. METHODS The immunomodulatory effect of peripherally administered HUCPVC on the expression profile of kynurenine pathway metabolites and enzymes was assessed in the plasma and brain of mice treated with LPS using LCMS and QPCR. An assessment of the glutamatergic system, including selected receptors, transporters and related proteins was also conducted by QPCR, immunohistochemistry and Western blot. RESULTS HUCPVC were found to modulate LPS-induced activation of KP enzymes and metabolites in the brain associated with neurotoxicity. Moreover, the reduced expression of the glutamatergic components due to LPS was also found to be significantly improved by HUCPVC. CONCLUSIONS The immunomodulatory properties of HUCPVC appear to confer neuroprotection, at least in part, through their ability to modulate the KP in the brain. This KP modulation enhances neuroprotective regulators and downregulates neurotoxic consequences, including glutamate neurotoxicity, which is associated with neuroinflammation and depressive behavior.
Collapse
Affiliation(s)
- Fyyaz Siddiqui
- CReATe Fertility Centre, 790 Bay Street, Suite 1100, Toronto, ON, M5G 1N8, Canada.
| | - Denis Gallagher
- CReATe Fertility Centre, 790 Bay Street, Suite 1100, Toronto, ON, M5G 1N8, Canada
| | - Hannah Shuster-Hyman
- CReATe Fertility Centre, 790 Bay Street, Suite 1100, Toronto, ON, M5G 1N8, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Lianet Lopez
- CReATe Fertility Centre, 790 Bay Street, Suite 1100, Toronto, ON, M5G 1N8, Canada
| | | | - Clifford L Librach
- CReATe Fertility Centre, 790 Bay Street, Suite 1100, Toronto, ON, M5G 1N8, Canada.
- Department of Obstetrics and Gynecology, Toronto, Canada.
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
- Department of Physiology, University of Toronto, Toronto, ON, Canada.
| |
Collapse
|
|
10
|
Radford-Smith DE, Anthony DC. Prebiotic and Probiotic Modulation of the Microbiota-Gut-Brain Axis in Depression. Nutrients 2023; 15:nu15081880. [PMID: 37111100 PMCID: PMC10146605 DOI: 10.3390/nu15081880] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/07/2023] [Accepted: 04/10/2023] [Indexed: 04/29/2023] Open
Abstract
Emerging evidence demonstrates that alterations to the gut microbiota can affect mood, suggesting that the microbiota-gut-brain (MGB) axis contributes to the pathogenesis of depression. Many of these pathways overlap with the way in which the gut microbiota are thought to contribute to metabolic disease progression and obesity. In rodents, prebiotics and probiotics have been shown to modulate the composition and function of the gut microbiota. Together with germ-free rodent models, probiotics have provided compelling evidence for a causal relationship between microbes, microbial metabolites, and altered neurochemical signalling and inflammatory pathways in the brain. In humans, probiotic supplementation has demonstrated modest antidepressant effects in individuals with depressive symptoms, though more studies in clinically relevant populations are needed. This review critically discusses the role of the MGB axis in depression pathophysiology, integrating preclinical and clinical evidence, as well as the putative routes of communication between the microbiota-gut interface and the brain. A critical overview of the current approaches to investigating microbiome changes in depression is provided. To effectively translate preclinical breakthroughs in MGB axis research into novel therapies, rigorous placebo-controlled trials alongside a mechanistic and biochemical understanding of prebiotic and probiotic action are required from future research.
Collapse
Affiliation(s)
- Daniel E Radford-Smith
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
- Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
- Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford OX3 7JX, UK
| | - Daniel C Anthony
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
| |
Collapse
|
|
11
|
Tian JS, Zhao YH, Ling-Hu T, Wu WZ, Wang XX, Ji C, Zhao WD, Han YM, Qin XM. A novel insight for high-rate and low-efficiency glucose metabolism in depression through stable isotope-resolved metabolomics in CUMS-induced rats. J Affect Disord 2023; 331:121-129. [PMID: 36948469 DOI: 10.1016/j.jad.2023.03.061] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 03/12/2023] [Accepted: 03/18/2023] [Indexed: 03/24/2023]
Abstract
BACKGROUND Existing research has suggested that depression results in disorders of glucose metabolism in the organism which causing insufficient energy supply. However, the overall changes in glucose metabolism that arise from depression have not been clarified. METHODS In this study, the depression-like behavior in chronically unpredictable mild stressed rats was investigated, and the fate of glucose was tracked through isotope tracing and mass spectrometry, with a focus on metabolite changes in cecal contents. RESULTS As indicated by the results, the isotopic results of cecal contents can indicate the metabolic end of the organism. Moreover, the TCA cycle activity was notably reduced, and the gluconeogenesis pathway was abnormally up-regulated in the CUMS-induced rats. The organism expedited other glucose metabolism pathways to make up for the insufficiency of energy. As a result, the activity of the inefficient glycolysis pathway was increased. LIMITATIONS Existing research has only investigated the metabolism of 13C-glucose, and lipids and proteins have been rarely explored. CONCLUSIONS The chronic unpredictable mild stress can inhibit the entry of pyruvate into mitochondria in SD rats, such that the activity of TCA is reduced, and insufficient energy supply is caused. The organism is capable of expediting other glucose metabolism rate pathways to make up for the insufficiency of energy, whereas it still cannot compensate for the loss of energy. As a result, CUMS-induced rats exhibited high-rate and low-efficiency glucose metabolism.
Collapse
Affiliation(s)
- Jun-Sheng Tian
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan 030006, China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Shanxi University, Taiyuan 030006, China; The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China
| | - Yun-Hao Zhao
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan 030006, China
| | - Ting Ling-Hu
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan 030006, China
| | - Wen-Ze Wu
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan 030006, China
| | - Xian-Xian Wang
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan 030006, China
| | - Cui Ji
- School of Physical Education, Shanxi University, Taiyuan 030006, China
| | - Wei-di Zhao
- School of Physical Education, Shanxi University, Taiyuan 030006, China
| | - Yu-Mei Han
- School of Physical Education, Shanxi University, Taiyuan 030006, China
| | - Xue-Mei Qin
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan 030006, China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Shanxi University, Taiyuan 030006, China; The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China.
| |
Collapse
|
|
12
|
Wertheim BM, Wang RS, Guillermier C, Hütter CV, Oldham WM, Menche J, Steinhauser ML, Maron BA. Proline and glucose metabolic reprogramming supports vascular endothelial and medial biomass in pulmonary arterial hypertension. JCI Insight 2023; 8:163932. [PMID: 36626231 PMCID: PMC9977503 DOI: 10.1172/jci.insight.163932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
In pulmonary arterial hypertension (PAH), inflammation promotes a fibroproliferative pulmonary vasculopathy. Reductionist studies emphasizing single biochemical reactions suggest a shift toward glycolytic metabolism in PAH; however, key questions remain regarding the metabolic profile of specific cell types within PAH vascular lesions in vivo. We used RNA-Seq to profile the transcriptome of pulmonary artery endothelial cells (PAECs) freshly isolated from an inflammatory vascular injury model of PAH ex vivo, and these data were integrated with information from human gene ontology pathways. Network medicine was then used to map all aa and glucose pathways to the consolidated human interactome, which includes data on 233,957 physical protein-protein interactions. Glucose and proline pathways were significantly close to the human PAH disease module, suggesting that these pathways are functionally relevant to PAH pathobiology. To test this observation in vivo, we used multi-isotope imaging mass spectrometry to map and quantify utilization of glucose and proline in the PAH pulmonary vasculature at subcellular resolution. Our findings suggest that elevated glucose and proline avidity underlie increased biomass in PAECs and the media of fibrosed PAH pulmonary arterioles. Overall, these data show that anabolic utilization of glucose and proline are fundamental to the vascular pathology of PAH.
Collapse
Affiliation(s)
| | - Rui-Sheng Wang
- Division of Cardiovascular Medicine, Department of Medicine.,Channing Division of Network Medicine, Department of Medicine; and
| | - Christelle Guillermier
- Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Center for NanoImaging, Cambridge, Massachusetts, USA
| | - Christiane Vr Hütter
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.,Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna, Austria.,Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and the Medical University of Vienna, Vienna, Austria
| | - William M Oldham
- Division of Pulmonary and Critical Medicine, Department of Medicine
| | - Jörg Menche
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.,Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna, Austria.,Faculty of Mathematics, University of Vienna, Vienna, Austria
| | - Matthew L Steinhauser
- Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Center for NanoImaging, Cambridge, Massachusetts, USA.,Division of Cardiovascular Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.,Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | | |
Collapse
|
|
13
|
Low levels of serum LDH are associated with depression and suicide attempts. Gen Hosp Psychiatry 2022; 79:42-49. [PMID: 36265388 DOI: 10.1016/j.genhosppsych.2022.10.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 10/06/2022] [Accepted: 10/06/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND A huge body of evidence has signaled a correlation between adult depression and energy metabolism. The key links are the energy supply and substrates for brain energy metabolism and the crucial signaling molecule lactate. Nevertheless, the association between lactate metabolism and depression remains elusive. OBJECTIVE The primary objective of this study was to explore the difference in serum LDH levels between patients with major depressive disorder (MDD) and the normal population and to determine whether LDH can be employed as a predictor of suicide attempt (SA) in MDD patients. METHODS Serum LDH levels were measured in 232 patients with MDD and 110 healthy controls. Depressive symptoms were assessed using the 24-item Hamilton Depression Scale (HAMD-24). The data were collected and analyzed with SPSS 22.0. RESULTS The serum LDH level of the control group was (196.50 ± 34.40) U/L, while that of the MDD group was (177.94 ± 25.89) U/L (P < 0.001). Notably, the LDH level [(169.96 ± 25.31) U/L] in the SA group was significantly lower than that in the control and non-SA groups [(181.25 ± 25.47) U/L] (P < 0.01); There was no significant correlation with HAMD-24 score (P > 0.05). Collectively, this study demonstrated that a decrease in serum LDH levels is an independent risk factor for SA in MDD patients. CONCLUSION Our results imply that a decrease in LDH levels may be associated with MDD and suicidal behaviors. Early identification of suicide risk and evaluation of the prognosis of depression is critical.
Collapse
|
|
14
|
Wang J, Sun YC. Revealing the pharmacological effect and mechanism of darutoside on gouty arthritis by liquid chromatography/mass spectrometry and metabolomics. Front Mol Biosci 2022; 9:942303. [PMID: 36090056 PMCID: PMC9448993 DOI: 10.3389/fmolb.2022.942303] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Darutoside is a diterpenoids compound with significant anti-inflammatory activity, however the pharmacological action and mechanism are still unclear. Metabolomics strategy was used to uncovering the pharmacological action and effective mechanism of darutoside against acute gouty arthritis rats. Liquid chromatography coupled with mass spectrometry technique was performed to explore the serum metabolites and potential pathways. We found that darutoside can up-regulate the level of glutamate, alanine, chenodeoxycholic acid, 1-methyladenosine, aspartic acid, citric acid, and down-regulate the level of valine, isoleucine, glutamine, alanyl-threonine, pyruvic acid, gamma-aminobutyric acid, uric acid. Metabolic pathway analysis showed that the therapeutic effect of darutoside was involved in amino acid metabolism, sugar metabolism, fatty acid metabolism, energy metabolism, purine metabolism and butanoate metabolism. It indicated that darutoside protect against acute gouty arthritis by regulating the expression of the key protein targets. It revealed that the mechanism of darutoside on acute gouty arthritis, which may be leading to the changes of serum metabolites, metabolic pathways and key protein targets to improve immune system response, inhibit oxidative stress and inflammatory response. It provides a novel method for molecular mechanisms of natural product in the disease treatment.
Collapse
Affiliation(s)
- Jing Wang
- School Hospital, Harbin University of Science and Technology, Harbin, China
| | - Yan-Chun Sun
- School Hospital, Harbin University of Science and Technology, Harbin, China
- Heilongjiang River Fisheries Research Institute of Chinese Academy of Fishery Sciences /Laboratory of Quality & Safety Risk Assessment for Aquatic Products (Harbin), Ministry of Agriculture and Rural Areas, Harbin, China
- *Correspondence: Yan-Chun Sun,
| |
Collapse
|
|
15
|
Schapovalova O, Gorlova A, de Munter J, Sheveleva E, Eropkin M, Gorbunov N, Sicker M, Umriukhin A, Lyubchyk S, Lesch KP, Strekalova T, Schroeter CA. Immunomodulatory effects of new phytotherapy on human macrophages and TLR4- and TLR7/8-mediated viral-like inflammation in mice. Front Med (Lausanne) 2022; 9:952977. [PMID: 36091684 PMCID: PMC9450044 DOI: 10.3389/fmed.2022.952977] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/15/2022] [Indexed: 11/17/2022] Open
Abstract
Background While all efforts have been undertaken to propagate the vaccination and develop remedies against SARS-CoV-2, no satisfactory management of this infection is available yet. Moreover, poor availability of any preventive and treatment measures of SARS-CoV-2 in economically disadvantageous communities aggravates the course of the pandemic. Here, we studied a new immunomodulatory phytotherapy (IP), an extract of blackberry, chamomile, garlic, cloves, and elderberry as a potential low-cost solution for these problems given the reported efficacy of herbal medicine during the previous SARS virus outbreak. Methods The key feature of SARS-CoV-2 infection, excessive inflammation, was studied in in vitro and in vivo assays under the application of the IP. First, changes in tumor-necrosis factor (TNF) and lnteurleukin-1 beta (IL-1β) concentrations were measured in a culture of human macrophages following the lipopolysaccharide (LPS) challenge and treatment with IP or prednisolone. Second, chronically IP-pre-treated CD-1 mice received an agonist of Toll-like receptors (TLR)-7/8 resiquimod and were examined for lung and spleen expression of pro-inflammatory cytokines and blood formula. Finally, chronically IP-pre-treated mice challenged with LPS injection were studied for "sickness" behavior. Additionally, the IP was analyzed using high-potency-liquid chromatography (HPLC)-high-resolution-mass-spectrometry (HRMS). Results LPS-induced in vitro release of TNF and IL-1β was reduced by both treatments. The IP-treated mice displayed blunted over-expression of SAA-2, ACE-2, CXCL1, and CXCL10 and decreased changes in blood formula in response to an injection with resiquimod. The IP-treated mice injected with LPS showed normalized locomotion, anxiety, and exploration behaviors but not abnormal forced swimming. Isoquercitrin, choline, leucine, chlorogenic acid, and other constituents were identified by HPLC-HRMS and likely underlie the IP immunomodulatory effects. Conclusions Herbal IP-therapy decreases inflammation and, partly, "sickness behavior," suggesting its potency to combat SARS-CoV-2 infection first of all via its preventive effects.
Collapse
Affiliation(s)
- Olesia Schapovalova
- Caparica Faculdade de Ciencias e Tecnologia da Universidade Nova de Lisboa, NOVA Lisbon University, Lisbon, Portugal
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University and Neuroplast BV, Maastricht, Netherlands
| | - Anna Gorlova
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University and Neuroplast BV, Maastricht, Netherlands
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov First Moscow State Medical University, Moscow, Russia
- Laboratory of Cognitive Dysfunctions, Federal Budgetary Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Johannes de Munter
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University and Neuroplast BV, Maastricht, Netherlands
| | - Elisaveta Sheveleva
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov First Moscow State Medical University, Moscow, Russia
- Laboratory of Cognitive Dysfunctions, Federal Budgetary Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Mikhail Eropkin
- Department of Etiology and Epidemiology, Smorodintsev Research Institute of Influenza, St. Petersburg State University, Saint Petersburg, Russia
| | - Nikita Gorbunov
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Michail Sicker
- Rehabilitation Research Unit of Clinic of Bad Kreuzbach, Bad Kreuzbach, Germany
| | - Aleksei Umriukhin
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Sergiy Lyubchyk
- Caparica Faculdade de Ciencias e Tecnologia da Universidade Nova de Lisboa, NOVA Lisbon University, Lisbon, Portugal
- EIGES Center, Universidade Lusofona, Lisboa, Portugal
| | - Klaus-Peter Lesch
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University and Neuroplast BV, Maastricht, Netherlands
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Tatyana Strekalova
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University and Neuroplast BV, Maastricht, Netherlands
- Laboratory of Cognitive Dysfunctions, Federal Budgetary Institute of General Pathology and Pathophysiology, Moscow, Russia
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | | |
Collapse
|
|
16
|
Matisz C, Gruber A. Neuroinflammatory remodeling of the anterior cingulate cortex as a key driver of mood disorders in gastrointestinal disease and disorders. Neurosci Biobehav Rev 2022; 133:104497. [DOI: 10.1016/j.neubiorev.2021.12.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 11/10/2021] [Accepted: 12/09/2021] [Indexed: 02/08/2023]
|
|
17
|
Yates AG, Weglinski CM, Ying Y, Dunstan IK, Strekalova T, Anthony DC. Nafamostat reduces systemic inflammation in TLR7-mediated virus-like illness. J Neuroinflammation 2022; 19:8. [PMID: 34991643 PMCID: PMC8734544 DOI: 10.1186/s12974-021-02357-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 12/14/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infection are lacking. In this study, we examined the potential of the dual TLR7/8 agonist R848 to mimic the host response to an ssRNA virus infection and the associated behavioural response. In addition, we evaluated the anti-inflammatory effects of nafamostat in this model. METHODS CD-1 mice received an intraperitoneal injection of R848 (200 μg, prepared in DMSO, diluted 1:10 in saline) or diluted DMSO alone, and an intravenous injection of either nafamostat (100 μL, 3 mg/kg in 5% dextrose) or 5% dextrose alone. Sickness behaviour was determined by temperature, food intake, sucrose preference test, open field and forced swim test. Blood and fresh liver, lung and brain were collected 6 h post-challenge to measure markers of peripheral and central inflammation by blood analysis, immunohistochemistry and qPCR. RESULTS R848 induced a robust inflammatory response, as evidenced by increased expression of TNF, IFN-γ, CXCL1 and CXCL10 in the liver, lung and brain, as well as a sickness behaviour phenotype. Exogenous administration of nafamostat suppressed the hepatic inflammatory response, significantly reducing TNF and IFN-γ expression, but had no effect on lung or brain cytokine production. R848 administration depleted circulating leukocytes, which was restored by nafamostat treatment. CONCLUSIONS Our data indicate that R848 administration provides a useful model of ssRNA virus infection, which induces inflammation in the periphery and CNS, and virus infection-like illness. In turn, we show that nafamostat has a systemic anti-inflammatory effect in the presence of the TLR7/8 agonist. Therefore, the results indicate that nafamostat has anti-inflammatory actions, beyond its ability to inhibit TMPRSS2, that might potentiate its anti-viral actions in pathologies such as COVID-19.
Collapse
Affiliation(s)
- Abi G Yates
- Department of Pharmacology, The University of Oxford, Mansfield Road, Oxford, UK
- School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
| | - Caroline M Weglinski
- Department of Pharmacology, The University of Oxford, Mansfield Road, Oxford, UK
| | - Yuxin Ying
- Department of Pharmacology, The University of Oxford, Mansfield Road, Oxford, UK
| | - Isobel K Dunstan
- Department of Pharmacology, The University of Oxford, Mansfield Road, Oxford, UK
| | - Tatyana Strekalova
- Sechenov First Moscow State Medical University, Moscow, Russia
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Daniel C Anthony
- Department of Pharmacology, The University of Oxford, Mansfield Road, Oxford, UK.
- Sechenov First Moscow State Medical University, Moscow, Russia.
- University of Southern Denmark, Odense, Denmark.
| |
Collapse
|
|
18
|
Jo D, Song J. Irisin Acts via the PGC-1α and BDNF Pathway to Improve Depression-like Behavior. Clin Nutr Res 2021; 10:292-302. [PMID: 34796134 PMCID: PMC8575642 DOI: 10.7762/cnr.2021.10.4.292] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 09/09/2021] [Accepted: 09/09/2021] [Indexed: 11/19/2022] Open
Abstract
Depression is the most prevalent psychiatric disorder experienced by the world's population. Mechanisms associated with depression-like behavior have not been fully investigated. Among the therapeutic solution for depression, exercise is considered an important regulator attenuating depressive neuropathology. Exercise has been reported to boost the secretion of myokines such as irisin and myostatin in skeletal muscles. Myokines secreted during exercise are involved in various cellular responses including the endocrine and autocrine systems. Especially, irisin as a cleaved version of fibronectin domain-containing protein 5 has multiple functions such as white fat-browning, energy expenditure increase, anti-inflammatory effects, and mitochondrial function improvement in both systemic circulation and central nervous system. Furthermore, irisin activates energy metabolism-related signaling peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and memory formation-related signaling brain-derived neurotrophic factor involved in depression. However, the role and mechanism of irisin in depression disorder is not obvious until now. Here, we review recent evidences regarding the therapeutic effect of irisin in depression disorder. We suggest that irisin is a key molecule that suppresses several neuropathological mechanisms involved in depression.
Collapse
Affiliation(s)
- Danbi Jo
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Korea.,Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
| | - Juhyun Song
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Korea.,Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
| |
Collapse
|
|
19
|
Emerging application of metabolomics on Chinese herbal medicine for depressive disorder. Biomed Pharmacother 2021; 141:111866. [PMID: 34225013 DOI: 10.1016/j.biopha.2021.111866] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/20/2021] [Accepted: 06/28/2021] [Indexed: 12/13/2022] Open
Abstract
Depressive disorder is a kind of emotional disorder that is mainly manifested with spontaneous and persistent low mood. Its etiology is complex and still not fully understood. Metabolomics, an important part of system biology characterized by its integrity and systematicness, analyzes endogenous metabolites of small molecules in vivo and examines the metabolic status of the organism. It is widely used in the field of disease research for its unique advantage in the disease molecular marker discovering Due to fewer adverse reactions and high safety, Chinese herbal medicine (CHM) has great advantages in the treatment of chronic diseases including depression. Metabolomics has been gradually applied to the efficacy evaluation of CHM in treatment of depression and the metabolomics analysis exhibits a systemic metabolic shift in amino acids (such as alanine, glutamic acid, valine, etc.), organic acids (lactic acid, citric acid, stearic acid, palmitic acid, etc.), and sugars, amines, etc. These differential metabolites are mainly involved in energy metabolism, amino acid metabolism, lipid metabolism, etc. In this review, we have exemplified the study of CHM in animals or clinics on the depression, and revealed that CHM treatment has significantly changed the metabolic disorders associated with depression, promoting metabolic network reorganization through restoring of key metabolites, and metabolic pathways, which may be the main mechanism basis of CHM's treatment on depression. Besides, we further envisioned the future application of metabolomics in the study of CHM treatment of depression.
Collapse
|
|
20
|
Gu X, Ke S, Wang Q, Zhuang T, Xia C, Xu Y, Yang L, Zhou M. Energy metabolism in major depressive disorder: Recent advances from omics technologies and imaging. Biomed Pharmacother 2021; 141:111869. [PMID: 34225015 DOI: 10.1016/j.biopha.2021.111869] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 06/06/2021] [Accepted: 06/28/2021] [Indexed: 02/08/2023] Open
Abstract
Major depressive disorder (MDD) is a serious psychiatric disorder that associated with high rate of disability and increasing suicide rate, and the pathogenesis is still unclear. Many researches showed that the energy metabolism of patients with depression is impaired, which may be the direction of depression treatment. In this review, we focus on the "omics" technologies such as genomics, proteomics, transcriptomics and metabolomics, as well as imaging, and the progress on energy metabolism of MDD. These findings indicate that abnormal energy metabolism is one of the important mechanisms for the occurrence and development of depression. Although the research on various mechanisms of depression is still ongoing, the rapid development of new technologies and the joint use of various technologies will help to clarify the pathogenesis of depression and explore efficient diagnosis and treatment methods.
Collapse
Affiliation(s)
- Xinyi Gu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Shuang Ke
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qixue Wang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tongxi Zhuang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Chenyi Xia
- Department of Physiology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ying Xu
- Department of Physiology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Yang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mingmei Zhou
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| |
Collapse
|
|
21
|
Kan L, Guo F, Liu Y, Pham VH, Guo Y, Wang Z. Probiotics Bacillus licheniformis Improves Intestinal Health of Subclinical Necrotic Enteritis-Challenged Broilers. Front Microbiol 2021; 12:623739. [PMID: 34084155 PMCID: PMC8168541 DOI: 10.3389/fmicb.2021.623739] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 03/25/2021] [Indexed: 12/18/2022] Open
Abstract
Necrotic enteritis infection poses a serious threat to poultry production, and there is an urgent need for searching effective antibiotic alternatives to control it with the global ban on in-feed antibiotics. This study was conducted to investigate the effects of dietary Bacillus licheniformis replacing enramycin on the growth performance and intestinal health of subclinical necrotic enteritis (SNE)-challenged broilers. In total, 504 1-day-old Arbor Acres male chickens were selected and subsequently assigned into three treatments, including PC (basal diet + SNE challenge), PA (basal diet extra 10 mg/kg enramycin + SNE challenge), and PG (basal diet extra 3.20 × 109 and 1.60 × 109 CFU B. licheniformis per kg diet during 1-21 days and 22-42 days, respectively + SNE challenge). Results showed that B. licheniformis significantly decreased the intestinal lesion scores and down-regulated the Claudin-3 mRNA levels in jejunum of SNE-infected broilers on day 25, but increased the mucin-2 gene expression in broilers on day 42. In addition, B. licheniformis significantly up-regulated the mRNA levels of TRIF and NF-κB of SNE-challenged broilers compared with the control group on day 25 and TLR-4, TRIF compared with the control and the antibiotic group on day 42. The mRNA expression of growth factors (GLP-2 and TGF-β2) and HSPs (HSP60, HSP70, and HSP90) were up-regulated in B. licheniformis supplementary group on days 25 and 42 compared with group PC. LEfSe analysis showed that the relative abundance of Lachnospiraceae_UCG_010 was enriched in the PG group; nevertheless, Clostridiales_vadinBB60 and Rnminococcaceae_NK4A214 were in PA. PICRUSt analysis found that the metabolism of cofactors and vitamins, amino acid metabolism, and carbohydrate metabolism pathways were enriched, whereas energy metabolism, membrane transport, cell motility, and lipid metabolism were suppressed in B. licheniformis-supplemented groups as compared with the PC control. In conclusion, dietary supplementation of B. licheniformis alleviated the intestinal damage caused by SNE challenge that coincided with modulating intestinal microflora structure and barrier function as well as regulating intestinal mucosal immune responses.
Collapse
Affiliation(s)
| | | | | | | | | | - Zhong Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| |
Collapse
|
|
22
|
Kaukas L, Krieg J, Collins-Praino L, Corrigan F. Effects of Remote Immune Activation on Performance in the 5-Choice Serial Reaction Time Task Following Mild Traumatic Brain Injury in Adolescence. Front Behav Neurosci 2021; 15:659679. [PMID: 33867953 PMCID: PMC8046921 DOI: 10.3389/fnbeh.2021.659679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/12/2021] [Indexed: 11/17/2022] Open
Abstract
In adult pre-clinical models, traumatic brain injury (TBI) has been shown to prime microglia, exaggerating the central inflammatory response to an acute immune challenge, worsening depressive-like behavior, and enhancing cognitive deficits. Whether this phenomenon exists following mTBI during adolescence has yet to be explored, with age at injury potentially altering the inflammatory response. Furthermore, to date, studies have predominantly examined hippocampal-dependent learning domains, although pre-frontal cortex-driven functions, including attention, motivation, and impulsivity, are significantly affected by both adolescent TBI and acute inflammatory stimuli. As such, the current study examined the effects of a single acute peripheral dose of LPS (0.33 mg/kg) given in adulthood following mTBI in mid-adolescence in male Sprague–Dawley rats on performance in the 5-choice serial reaction time task (5-CSRTT). Only previously injured animals given LPS showed an increase in omissions and reward collection latency on the 5-CSRTT, with no effect noted in sham animals given LPS. This is suggestive of impaired motivation and a prolonged central inflammatory response to LPS administration in these animals. Indeed, morphological analysis of myeloid cells within the pre-frontal cortex, via IBA1 immunohistochemistry, found that injured animals administered LPS had an increase in complexity in IBA1+ve cells, an effect that was seen to a lesser extent in sham animals. These findings suggest that there may be ongoing alterations in the effects of acute inflammatory stimuli that are driven, in part by increased reactivity of microglial cells.
Collapse
Affiliation(s)
- Lola Kaukas
- Head Injury Laboratory, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Justin Krieg
- Head Injury Laboratory, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Lyndsey Collins-Praino
- Head Injury Laboratory, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Frances Corrigan
- Head Injury Laboratory, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| |
Collapse
|